Understanding How Adjuvants Boost Immune Responses

What have researchers learned about the use of substances called adjuvants that can augment the response to vaccination?

A number of different strategies have been used to develop existing vaccines. Some, such as those that prevent influenza or pertussis, contain a whole-killed version of the virus or bacteria itself. Others, including the oral polio vaccine or the combination vaccine that protects against measles, mumps, and rubella, contain weakened or attenuated forms of the viruses against which the vaccines are designed to protect. While this strategy has proven safe for many vaccines, whole-killed or attenuated HIV vaccines are not considered viable strategies partly because of concerns that the virus would mutate and regain its ability to cause disease, therefore making it unsafe. Rather than containing HIV in its entirety, AIDS vaccine candidates contain non-infectious fragments of HIV’s genetic material.

Unfortunately, these gene fragments used in HIV vaccine candidates (referred to as antigens) are not as effective at stimulating the immune system as whole-killed or attenuated pathogens. One way to boost the immune response to these vaccine candidates is to add an adjuvant (see VAX October 2004 Primer on Understanding Vaccine Adjuvants). The word adjuvant comes from the Latin word adiuvare, which means to help, and adjuvants have been called a vaccine’s little helper. These substances work by mimicking the danger signals triggered by actual pathogens, thereby activating the body’s innate immune response—the first line of defense against viruses and bacteria—which in turn activate the body’s adaptive immune responses (see VAX December 2008 Primer on Understanding Innate Immunity and HIV). Both innate and adaptive immune responses are thought to be important in vaccine-induced protection. Some adjuvants boost the immune responses enough that less of the vaccine is required to provide protection.

Many licensed vaccines use adjuvants, the most common being alum, which consists of insoluble aluminum salts. Another adjuvant called AS04—a mixture of alum and a derivative of bacterial endotoxin—is used in a recently licensed vaccine against human papillomavirus (HPV) and was the first non-alum adjuvant to be approved in the US. Meanwhile, another adjuvant, MF59, which contains biodegradable oil, is used in influenza vaccines in Europe.

Innate immunity

Interestingly, while alum has been used as an adjuvant for over 80 years, scientists still do not have a clear understanding of exactly how it works. But the understanding of how adjuvants work is improving as researchers develop a better understanding of innate immunity. In recent years, scientists have learned a lot about this arm of the immune system through the identification of specific proteins on cells, known as receptors, which control interactions between cells and their environment. Dendritic cells and macrophages—two types of innate immune cells that are the body’s first responders—rely on these protein receptors to sense pathogens and alert the immune system of their presence.

The first class of protein receptors, called toll-like receptors, was identified about 15 years ago. Since then, researchers have identified 10 human toll-like receptors as well as other receptors that specifically recognize retroviruses, such as HIV. Scientists say identifying and learning about these receptors will enable them to design new and improved adjuvants that work in a more systematic way, which could then lead to an improved stimulation of innate immune responses by adjuvants, and ultimately a more sustained immune response to vaccination.

HIV vaccine adjuvants

Because AIDS vaccine candidates containing fragments of HIV genes may not provoke as robust an immune response, scientists think some AIDS vaccine candidates are likely to require adjuvants. The exception is viral vector-based approaches, which use modified, non-infectious viruses other than HIV to carry fragments of HIV’s genetic material. These candidates typically do not require an adjuvant because they are thought to stimulate stronger innate immune responses.

Several of the AIDS vaccine candidates that have been tested in clinical trials so far have been administered along with the adjuvant alum, most notably VaxGen’s AIDSVAX vaccine candidate (a genetically engineered version of HIV’s gp120 surface protein) that was used in the VAX003 and 004 Phase III trials in the US and Thailand, as well as the RV144 efficacy trial in Thailand.

However, evidence is building that other adjuvants may be more effective than alum. The follow-up trials of RV144 will likely use MF59 rather than alum because studies of several adjuvants found that alum produced the lowest level of antibody responses. Researchers are also studying another adjuvant, called PolyICLC, which binds to a toll-like receptor and another receptor inside dendritic cells, in a Phase I AIDS vaccine trial.

Other adjuvants are also being evaluated in preclinical studies, including one that is designed to induce innate and mucosal immune responses, which are considered important for protection against HIV because it is most often transmitted sexually.